Human apolipoprotein (Apo) E includes three common isoforms known as ApoE2, ApoE3 and ApoE4. ApoE3 is considered to be the normal isoform, while ApoE2 and ApoE4 are dysfunctional. Individuals carrying defective isoforms of ApoE develop hypercholesterolemia and atherosclerosis. Similarly, ApoE null knockout (ApoE-/-) mice suffer from hypercholesterolemia and atherosclerosis resembling the human disease. The hypercholesterolemia in ApoE-deficient patients and mouse models results mainly from an increased plasma level of remnant lipoproteins that contain ApoB48. Previous studies from our laboratory demonstrate that the remnant lipoproteins obtained from ApoE-/- mice is able to transform macrophages into foam cells, and that foam cell formation induced by ApoE-free remnant lipoproteins coincides with an enhanced phosphorylation of eukaryotic translation initiation factor 21 (eIF-21), which is a cellular event related to endoplasmic reticulum (ER) stress. We also observed that inhibition of eIF-21 phosphorylation attenuated ApoE-free remnant lipoprotein-induced foam cell formation. Moreover, we observed that mouse remnant lipoproteins enriched with defective isofoms of human ApoE, especially those enriched with ApoE4, induced cholesterol accumulation and eIF-21 phosphorylation in macrophages. It is highly likely that in the absence of, or deficiency in, ApoE, interaction of remnant lipoproteins with macrophages activates ER stress-related signaling pathways, which in turn regulate the expression of genes whose encoded products contribute to foam cell formation. In this project, we will test a hypothesis that the remnant lipoproteins that contain defective isoforms of human ApoE induce foam cell formation via a mechanism involving induction of ER stress. We will test this hypothesis with three specific aims. Specific aim 1 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE regulate the expression of genes related to foam cell formation. Specific aim 2 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE regulate gene expression by activation of ER stress-related signaling pathways. Specific aim 3 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE induce foam cell formation by activation of ER stress-related signaling pathways. If our hypothesis is correct, inhibition of ER stress-related signaling pathways would attenuate ApoE-deficient remnant lipoprotein-induced changes in macrophage lipid catabolism and foam cell formation-related gene expression, and suppress foam cell formation.